CN106068120A - Use the method that radio frequency and lossy coated bead manufacture tablet - Google Patents

Abstract

On the one hand, the present invention relates to the method for manufacturing the tablet comprising at least one pharmaceutically active agents, said method comprising the steps of: apply radio-frequency (RF) energy to sinter described powder blend into described tablet to powder blend, wherein said powder blend comprises lossy coated bead and at least one pharmaceutically active agents described, wherein said lossy coated bead comprises base material, this base material is enclosed with the lossy coating containing at least one activator at least in part, wherein said base material has the Q-value more than 100, and described activator has the Q-value less than 75.

Description

Use the method that radio frequency and lossy coated bead manufacture tablet

Background technology

It is used for oral medicine to provide the most in form of tablets.Tablet can swallowed whole, chew in mouth or in oral cavity Disintegrate.When using medicine, provided that the tablet of swallowed whole is infeasible, then it is typically employed in mouth the film chewed or dissolve Agent.When using chewable tablets, mastication contributes to making tablet particle fragmentation when disintegration of tablet, and can improve digestive tract Absorption rate.Pharmaceutically active agents is made to can be used for partial result and/or systemic absorption in local in mouth or in throat in hope In the case of, film agent is also advantageous.Film agent is additionally operable to improve the medicament administration situation of pediatric patient and gerontal patient.Quilt It is designed for before swallowing the film agent in intra-oral disintegration and is particularly useful for improving the compliance of pediatric patient.

In general, the film agent blend manufacture by compacted powder shape composition, it generally comprises pharmaceutically active agents, tune Taste agent and/or binding agent.Generally powder blend feeding is entered in the die cavity of tablet machine, by applying pressure initiation tablet. The hardness of gained tablet is directly related with the compatibility of composition in compaction pressure used and formula.The relatively film agent being easier to break by the teeth can The compaction pressure reduced is used to prepare.The tablet of gained is softer, but the most fragile, brittle and be prone to embrittlement, and disadvantageous It is to can relate to complicated and uneconomic procedure of processing.It is designed to the film agent of disintegrate in mouth in the case of not chewing Example at United States Patent (USP) No.5,464,632, No.5,223,264, No.5,178,878, No.6,589,554 and No.6,224, Disclosed in 905.

Need the oral cavity disintegration tablet chewed utilizing the efficient manufacture method of business to produce good looking appearance.Oral cavity disintegration tablet Agent can be suppressed and form (see for example United States Patent (USP) No.5223264 and No.5178878), but the density of these tablets may be relatively Height, thus possible needs 20 to 30 seconds could complete disintegrate in mouth.The oral cavity disintegration tablet of lyophilizing (see for example United States Patent (USP) No.6509040, No.5976577, No.5738875 and No.5631023) often density relatively low, therefore disintegrate is very fast.But, this A little tablets need the long period to be formed, and with the method for unit dose blister packs form direct freeze-drying tablet agent prescription only The one side making dosage form shapes.When using this freeze drying process, drug loading is the most limited.

The present invention relates to the new method for manufacturing tablet, such as utilize lossy coated bead to manufacture oral cavity disintegration tablet The method of agent (" ODT "), the most lossy coating contains for the activator by particles sintering piece agent.Owing to this method will Activator concentration, on particle surface, so the amount of the activator added in tablet can be reduced, and can improve the sintering of particle Situation, thus compare those by other similar approach U.S. Patent application the most in this paper No.2009/0060983, The tablet that No.2011/0071184 and No.2013/0295175 manufactures, improves the characteristic of tablet, such as improves friability, improvement Mouthfeel, disintegration rate of accelerating, raising pharmaceutically active agents carrying capacity and/or shortening manufacturing time.

Summary of the invention

On the one hand, the present invention relates to the method for manufacturing the tablet comprising at least one pharmaceutically active agents, described side Method comprises the following steps: apply radio-frequency (RF) energy to sinter described powder blend into described tablet, wherein to powder blend Described powder blend comprises lossy coated bead and at least one pharmaceutically active agents described, wherein said lossy bag Clothing particle comprises base material, and this base material is enclosed with the lossy coating containing at least one activator, Qi Zhongsuo at least in part State base material and there is the Q-value more than 100, and described activator has the Q-value less than 75.

On the other hand, the present invention relates to the method for manufacturing the tablet comprising at least one pharmaceutically active agents, described Method comprises the following steps: apply radio-frequency (RF) energy to powder blend, to sinter described powder blend into described tablet, its Described in powder blend comprise lossy coated bead and at least one pharmaceutically active agents described, wherein said lossy Coated bead comprises base material, and this base material is enclosed with the lossy coating containing at least one activator at least in part, wherein The Q-value of activator is less than the half of the Q-value of base material.

On the other hand, the tablet of sintering comprises lossy coated bead and at least one pharmaceutically active agents, its Described in lossy coated bead comprise base material, this base material is enclosed with damaging containing at least one activator at least in part The coating of consumption, wherein said base material has the Q-value more than 100, and described activator has the Q-value less than 75.

On the other hand, the tablet of sintering comprises lossy coated bead and at least one pharmaceutically active agents, its Described in lossy coated bead comprise base material, this base material is enclosed with damaging containing at least one activator at least in part The coating of consumption, wherein the Q-value of activator is less than the half of the Q-value of base material.

After reading detailed description of the invention and the claim of the present invention, other features and advantages of the present invention are by aobvious and easy See.

Detailed description of the invention

It is believed that those skilled in the art can make full use of the present invention on the basis of described herein.Following is embodied as Scheme is understood that into and is only used for illustrating, and limits remaining content of the present invention the most by any way.

Unless otherwise defined, all technical terms the most used herein and scientific terminology are respectively provided with art of the present invention Identical meanings known to those of ordinary skill.Additionally, by all publications mentioned above, patent application, patent and other ginsengs Examine document to be incorporated by reference herein.Except as otherwise noted, all percentage ratio the most used herein is by weight.

As it has been described above, on the one hand, the present invention relates to:

Powder blend

In one embodiment, tablet is by comprising at least one pharmaceutically active agents (as described herein), damaging The coated bead (as described herein) of consumption and the powder blend of other suitable excipient optional apply radio-frequency (RF) energy and make 's.In one embodiment, among the single particle that at least one pharmaceutically active agents described is housed inside in powder blend. In one embodiment, at least one pharmaceutically active agents described is housed inside among lossy coated bead.

In one embodiment, powder blend/tablet comprise at least 20 weight % (such as at least 50 weight %, all Such as at least 70 weight %) as described in lossy coated bead.

The suitably example of excipient includes but not limited to: filler, deicer, fluidizer, sweeting agent, flavoring agent and virtue Pastil, antioxidant, preservative, matter structure reinforcing agent, coloring agent, and the mixture of these materials.One or more one-tenth above-mentioned Divide and may be present on the same particle of powder blend.

The example of filler includes but not limited to starch, sugar alcohol, bulk sweetener, polyhydric alcohol, polymer and plasticizer.

In one embodiment, powder blend/tablet comprises deicer, such as starch and/or silicon dioxide.Powder The benefit that there is deicer in blend is, after applying radio-frequency (RF) energy, deicer can play and water is retained in powder Effect in blend.The example of starch includes but not limited to plant amylum (such as pea starch and corn starch), modified shallow lake Powder (such as pre-gelatinized starch, Acid modified starch or dextrinized starch) or derivatized starch (such as crosslinked starch, acetylated starch and Hydroxyalkyl starch).The example of silicon dioxide includes that pyrolytic silicon dioxide is (such as purchased from Maryland, USA Colombia Grace Company (Grace, Columbia, Maryland, USA)FP silicon dioxide), clay (such as bentonite, magnesium silicate Aluminum and Magnesiumaluminumsilicate).In one embodiment, powder blend/tablet comprises about 0.1 weight % to 10 weight % (such as About 0.1 weight % is to 2 weight %) described deicer.

The example of fluidizer includes but not limited to colloidal silica.

The example of the sweeting agent of the present invention includes but not limited to: high intensity sweetner, such as synthesis sugar or natural sugar；Artificial Sweeting agent, such as saccharin, saccharin sodium, aspartame, acesulfame potassium, Africa hesperidium element, glycyrrhizin, sucralose, dihydrochalcone, Alitame, Synsepalum duleificum albumen, monellin and stevioside (stevside).

The example of flavoring agent and aromatic includes but not limited to: quintessence oil, including the flower chopped up, leaf, skin or smash the full fruit of slurry Distillation, solvent extractable matter or cold pressing thing, it contains the mixture of alcohol, ester, aldehyde and lactone；Essence, including the weak solution of quintessence oil Or it is blended into the mixture of the synthetic chemical that the natural flavor with fruit (such as Fructus Fragariae Ananssae, Fructus Rubi corchorifolii Immaturus and black gooseberry) mates； Brewing material and drinks (such as Cognac, Whiskey, rum, gin, sherry, bohr figure wine And wine) artificial flavoring agent and natural flavour mountaineous dose；Nicotiana tabacum L., coffee, tea, cocoa and Herba Menthae；Fruit juice, including from shampooing The fruit juice that such as Fructus Citri Limoniae, orange and Citrus aurantium Linn. squeeze out；Mentha viridis L, lavender, Ilicis Purpureae, Cortex Cinnamomi, cocoa, Rhizoma et radix valerianae, Radix Glycyrrhizae, menthol, Eucalyptus, Foeniculum vulgare；Nut (such as Semen arachidis hypogaeae, Cortex cocois radicis, Semen coryli heterophyllae, Semen Castaneae, Semen Juglandis, cola), Semen Armeniacae Amarum, dried Fructus Vitis viniferae；And powder, flour Or the plant material fraction including tobacco plant parts (such as Nicotiana plant part, its amount will not be obviously improved nicotine Level) and Rhizoma Zingiberis Recens.

The example of antioxidant includes but not limited to: tocopherol, ascorbic acid, sodium pyrosulfite, butylated hydroxytoluene, fourth Base hydroxyanisol, edetic acid and edetate, and the mixture of these materials.

The example of preservative includes but not limited to: citric acid, tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid and Pyrusussuriensis Acid, and the mixture of these materials.

The example of matter structure reinforcing agent includes but not limited to: pectin, poly(ethylene oxide) and carrageenin, and these materials Mixture.In one embodiment, the consumption of matter structure reinforcing agent is about 0.1 weight % to about 10 weight %.

In one embodiment of the invention, the particle mean size of powder blend is less than 500 microns, and the most about 50 is micro- Meter Zhi Yue 500 microns, the most about 50 microns to 300 microns.

Substantially free used herein, the meaning is less than 5%, such as less than 1%, such as less than 0.1%, the completeest Complete without (such as 0%).

In one embodiment, powder blend/tablet is substantially free of super-disintegrant.Super-disintegrant includes handing over Connection sodium carboxymethyl cellulose, Sodium Starch Glycolate and polyvinylpolypyrrolidone.It is substantially free of the suction of the compositions of super-disintegrant Aqueous reduces, so being conducive to improving mouthfeel, improving tablet stability.

In one embodiment, powder blend is substantially free of lubricant, such as magnesium stearate or stearic acid.Avoid It is with lubricator favourable for making in tablets, and reason is that known this material not only can slow down dissolution rate, also can make taste Become harmful effect (such as giving tablet bitterness pleasant impression).

Lossy coated bead

The present invention relates to comprise the powder blend/tablet of lossy coated bead, the most lossy coated bead Comprising base material, this base material is enclosed with the lossy coating containing at least one activator at least in part.Manufacturing sintered sheets During agent, this kind of particle can realize the controlled heat to powder blend.

The method manufacturing this kind of lossy coated bead includes but not limited to: top spray rubbing method, top spray granulation, Wurster rubbing method, tumbling barrel process, high shear granulation, spray drying method, spraying coagulation, hot-melt extruded method, micro encapsulation Method, disc type rubbing method, and extrusion spheronization.In one embodiment, coating material is dissolved into solution, then Spray on base material.In another embodiment, the method utilizing such as high shear granulation or spray drying method etc, will Coating material is blended with base material, then adds water in blend.In one embodiment, Coating Solution is aqueous solution, optionally Ground is containing other solvents.

In one embodiment, activator is cellulosic polymer.Suitably cellulosic polymer includes but not limited to: Hydroxypropyl cellulose, carboxyethyl cellulose, carboxymethyl cellulose, methylcellulose, hypromellose, and these materials Mixture.Other suitable activators include polysaccharide and protein, such as starch, modified starch, gelatinized starch and aqueous colloidal, Include but not limited to guar gum, carrageenin, maltodextrin, inulin and polyvinylpyrrolidone.Also have some other properly Activator include acrylic polymer, such as, but not limited to methacrylate, such as polymethyl methacrylate；Second Vinyl polymer, such as polyvinyl alcohol, polyvinyl pyrrolidone, Vinylcaprolactam homopolymer and polyvinyl acetate；These The copolymer of material, the copolymer of such as ethyl acrylate and methyl methacrylate；And polycaprolactone.An embodiment party In case, the weight average molecular weight of activator be less than 360,000 dalton, all such as less than 180,000 dalton.

In one embodiment, base material (such as the base material of particulate forms) is formed by selected from following material: starch, sugar, Sugar alcohol, dicalcium phosphate and microcrystalline Cellulose.Suitably sugar includes but not limited to sucrose, mannose, maltose, lactose, fructose, the right side Rotation sugar and Dextrose monohydrous.Suitably sugar alcohol includes but not limited to erythritol, Sorbitol, xylitol, mannitol and wheat Bud sugar alcohol.In one embodiment, base material comprises pharmaceutically active agents.In one embodiment, first is superscribed for base material One coating, then add lossy coating.

In one embodiment, the particle mean size of lossy coated bead is about 50 microns to about 500 microns, such as About 50 microns to about 400 microns, all such as from about 50 microns to about 300 microns.

Lossy coated bead is enclosed with coating at least in part.So-called " parcel at least in part ", the meaning is summary table At least 25% (such as at least 50%, such as at least 75%, such as 100%) of area is enclosed with coating.An embodiment In, in lossy coated bead, the amount of activator accounts at least about 0.25 weight % of lossy coated bead, the most at least About 0.4 weight %.In one embodiment, in lossy coated bead, the amount of activator accounts for lossy coated bead About 0.1 weight % to about 20 weight %, such as accounts for about 0.1 weight % of lossy coated bead to about 10 weight %, such as Account for about 0.1 weight % of lossy coated bead to about 2 weight %.

In one embodiment, lossy coated bead is aqueous.In this embodiment, dry at using 105 DEG C When loss till the dry weight until lossy coated bead is stable measures, lossy coated bead comprises at least The water of 0.1 weight %, the such as water of at least 0.3 weight %, the such as water of at least 0.5 weight %.In one embodiment, when When being measured by the dry loss before sintering, the water (such as water content) that lossy coated bead retains is at least 0.1 weight %, all such as from about 0.1 weight % to about 3 weight %, all such as from about 0.5 weight % is to about 2 weight %.

In one embodiment, coating contains more than one activator, such as two kinds of activators.An embodiment In, coating contains two kinds of polymer.

In one embodiment, coating contains plasticizer.Suitably plasticizer includes but not limited to: Polyethylene Glycol；Third Glycol；Glycerol；Sorbitol；Triethyl citrate；Tributyl citrate；Dibutyl sebacate；Vegetable oil such as Oleum Ricini, dish Seed oil, olive oil and sesame oil；The most poly-sorbitol ester of surfactant, sodium lauryl sulfate and dioctyl sodium sulfosuccinates acid Sodium；Glyceryl monoacetate；Glycerine 1,3-diacetate；Glycerol triacetate；Natural gum；Glyceryl triacetate；Citric acid acetyl three Butyl ester；Ethyl oxalate；Ethyl maleate.；Diethyl fumarate；Diethyl malonate；Dioctyl phthalate；Fourth Adipate；Tributyrin；Castor oil hydrogenated；Fatty acid；Substituted triglyceride and glyceride.An embodiment party In case, described coated bead contains the plasticizer of about 0.1 weight % to about 3 weight %.

In one embodiment, coating contains ion conductor, such as salt.The example of salt includes but not limited to slaine, Such as sodium salt, calcium salt, magnesium salt and potassium salt, such as sodium chloride and sodium citrate.In one embodiment, described coated bead contains There is about 0.1 weight % ion conductor to about 3 weight %.

Q-value

Dielectric constant character is resistant to measuring of the ability of electric field formation.For ease of in atmosphere material being compared, logical Often the way of custom is to describe the aerial dielectric constant of material, now dielectric constant be more specifically referred to as " relative permitivity " or €_r.This dielectric constant is the plural number represented by equation below:

€_r=e '-je "

Wherein, e ' (real) is dielectric constant (energy of storage), e " imaginary part of plural number () be dielectric loss or Dissipation factor (energy dissipated with form of heat).The ratio of dielectric loss (e ") and dielectric constant (e ') is referred to as loss angle tangent (tan δ) or power factor.Owing to material loss tangent under 27MHz used in food/medicine is minimum, so using The inverse (i.e. " Q-value ") of loss tangent is more convenient:

Q-value=e '/e "

For purposes of the invention, Q-value calculates for the frequency (such as 27MHz) of treated substance.Q-value is by physical property and chemical Matter affects, these character such as density (porosity/granularity), moisture (electrical conductivity), temperature and molecular polarizability.By this method Obtain measured value, the needs independently measuring and assessing these character can be eliminated.

Q-value is the least, and when applying external electromagnetic field, material is the most easily heated intensification.

In order to describe the component of the present invention, we are by material (such as, more weak to the response of external field thing higher for Q-value Matter) it is referred to as " passivator ".Passivator can be used to completely cut off or stop energy Flow.On the contrary, we are by material (example relatively low for Q-value As, the material that flux is higher) it is referred to as " activator ", because this material allows energy more to readily flow through, thus do more Merit.In order to describe the present invention, passivator has greater than about 100 Q-value of (all such as larger than 200 or more than 300), and activator has Q-value less than 75 (all such as less than 50).

The Q-value of various materials is listed in table 1 below.Employ when measuring Q-value and be connected to AgilentN5230C PNA-L's The HP 805C slotted line of port A and B (transmission mode) is as sample holder (taking off bracket).8592-is used under room temperature 60008E-cal correcting sample clamper and the coaxial wire rod of band N Connector, with eliminate measure loss during coaxial line/ The error that sample holder itself runs into.The method is referred to as " slotted line measurement method ".Except as otherwise noted, the most all set Slotted line measurement method is used to calculate e ', e described herein in being set to the frequency range of 26 to 28MHz (31 point resolution) " and Q Value, and by 27MHz data point record e ' and e " value.

Table 1

* notice that taste masking particle has coating, but this coating is without activator, and (that is, the Q-value recording ethyl cellulose is

98)。

In one embodiment, under 27MHz measure time, lossy coated bead (be blended before) e ' be to Few 1.4, such as at least 1.6, such as 1.7.In one embodiment, when measuring under 27MHz, lossy coated bead The e of (before being blended) " it is at least 0.009, such as at least 0.015, such as at least 0.0300.

The another kind of method measuring Q-value is to use custom-designed dielectric samples clamper, is hindered by Agilent 4294A Analysis resistant instrument is measured.Lightly powder is poured into equably in the specimen holder (puck) of sky, specimen holder is filled.Flatten excess Powder, obtains the end face of uniform ground.Powder/specimen holder uses thin capping (1mm), performs to measure for the first time.Follow-up Measurement in, take off capping, replace with next thicker capping.When changing capping, the thickness of capping all increases 1mm every time, Therefore powder is further consolidated.If powder is fully densified, be sealed on specimen holder placement shakiness, then test terminates.Then The powder of completely densified is weighed together with specimen holder (without capping).Then from specimen holder, take out powder, thoroughly clean Specimen holder, to avoid cross-contamination, weighs the weight of empty specimen holder the most again, obtains the base before and after the most different powder test Amount.This just can perform test with different powder densities, also can perform test on different temperature, humidity and separate date. The method is referred to as " parallel plate method ".The Q-value of various materials is listed in table 2 below.

Table 2

1: with trade namePurchased from EMD Millipore company

2: with trade name KollicoatPurchased from BASF AG

3: with trade nameRL30D is purchased from Evonik company

4: with trade nameK12 is purchased from Ashland company

It has been found that wrap up the base material containing one or more passivators with the coating containing one or more activators, obtain Particle in sintering process, show astonishing effect define the most resilient rapidly disintegrating dosage form.Although not wishing Hope and fettered by this theory, but activator is bound in advance synergism produced by passivator (base material), during sintering being made Joint efficiency exceedes simple additive effect.

Base material has more than 100, and all such as larger than 150, all such as larger than 200, all Q-value of such as larger than 400.Activator has little In 75, all such as less than 50, all Q-value of such as less than 30.In one embodiment, lossy coated bead has more than 50, All such as larger than 150, all Q-value of such as larger than 200.In one embodiment, powder blend has more than 50, all such as larger than 150, all Q-value of such as larger than 200.

Pharmaceutically active agents

Powder blend/the tablet of the present invention comprises the particle containing at least one pharmaceutically active agents.So-called " pharmaceutically active Agent ", refer to through FDA (U.S.Food and Drug Administration), Europe drug control Office (European Medicines Agency) or any succession entity of both license or approval are for oral medication disease Or the preparation (such as compound) of disease.Suitably pharmaceutically active agents includes but not limited to: analgesics, antiinflammatory, antipyretic, anti-group Amine agent, antibiotic (such as, antibacterial, antiviral agent and antifungal), antidepressants, antidiabetic, spasmolytic, appetite press down Preparation, bronchodilator, cardiovascular treatment agent (such as statins), central nervous system treatment agent, anti-tussive agents, subtract and fill Blood agent, diuretic, expectorant, gastro-intestinal therapeutic agent, anesthetis, mucolytic, muscle relaxant, osteoporosis therapy agent, emerging Put forth energy agent, nicotine and tranquilizer.

The suitably example of gastro-intestinal therapeutic agent includes but not limited to: antacid, such as pharmaceutically active agents (such as, the carbon containing aluminum Acid aluminum, aluminium hydroxide, mincid and aluminum phosphate), the pharmaceutically active agents of potassium-containing hydrogen salt, the pharmaceutically active agents of bismuth-containing (such as, bismuth aluminate, waltherite, bismuth subcarbonate, bismuth subgallate and basic bismuth nitrate), the pharmaceutically active agents of calcic (such as calcium carbonate), glycine, pharmaceutically active agents (such as, riopan, Magnesiumaluminumsilicate, magnesium carbonate, glycine containing magnesium Magnesium, magnesium hydroxide, magnesium oxide and magnesium trisilicate), phosphatic pharmaceutically active agents (such as, aluminum phosphate and calcium phosphate), containing potassium Pharmaceutically active agents (such as potassium bicarbonate), pharmaceutically active agents (such as sodium bicarbonate) containing sodium and silicate；Cathartic, as soft Just agent (such as many storehouses ester) and irritant laxative (such as bisacodyl)；Bisfentidine, as famotidine, ranitidine, Cimetidine and nizatidine；Proton pump inhibitor, such as omeprazole, R-lansoprazole, esomeprazole, pantoprazole, thunder shellfish Draw azoles and lansoprazole；Gastrointestinal cytoprotection agent, such as sucralfate and misoprostol；Gastrointestinal actuates medicine, such as prucalopride；For The antibiotic of helicobacter pylori (H.pylori), such as clarithromycin, amoxicillin, tetracycline and metronidazole；Diarrhea, as Basic bismuth salicylate, Kaolin, diphenoxylate and loperamide；Glycopyrrolate；Analgesics, such as U.S. husky amine；Bendectin, such as Ang Dan Department's fine jade, cyclizine, diphenhydramine, dimenhydrinate, meclizine, promethazine and hydroxyzine；Probiotic bacteria, includes but not limited to lactic acid Bacillus (lactobacilli)；Lactose enzyme；Racecadotril；And antiflatulent, if polydimethylsiloxane is (such as simethicone and west First silicone oil, including United States Patent (USP) No.4,906,478, No.5,275,822 and No.6, those disclosed in 103,260)；This The isomer of a little materials；And the pharmaceutically useful salt of these materials and prodrug (such as ester).

The suitably example of analgesic, antiinflammatory and antipyretic includes but not limited to: NSAID (non-steroidal anti-inflammatory drug) (NSAID), as Propanoic derivatives (such as, ibuprofen, naproxen, ketoprofen, flurbiprofen, fenbufen, fenoprofen, indoprofen, ketone Lip river Sweet smell, fluprofen, ratio the third sweet smell, carprofen, promazine, pranoprofen and suprofen) and COX inhibitor, such as celecoxib；To acetyl Amino phenols；Aspirin；Acetogenin, such as indomethacin, diclofenac, sulindac and tolmetin；Fenamic acid derivative, Such as mefenamic acid, meclofenamic acid and flufenamic acid；Biphenylcarboxylic acid derivatives, such as diflunisal and flufenisal；With former times health class, as Piroxicam, sudoxicam, isoxicam and meloxicam；The isomer of these materials；And these materials is pharmaceutically useful Salt and prodrug.

The example of antihistaminic and Decongestant includes but not limited to: brompheniramine, chloreyclizine, dexbrompheniramine, bromine are own Newly, phenindamine, pheniramine, pyrilamine, the thonzylamine, pripolidine, ephedrine, phenylephrine, False path Alkali, phenylpropanolamine, chlorphenamine, dextromethorphan, diphenhydramine, doxylamine, astemizole, teldane, Fexofenadine fourth, naphthalene First azoles woods, oxymetazoline, Montelukast, propylhexedrine, AH-611, Clemastime Fumartis, acrivastine, phenergan, oxomemazine, Mequitazine, buclizine, bromhexine, ketotifen, teldane, ebastine, oxatomide, xylometazoline, loratadine, Decarboxylation loratadine and cetirizine, the isomer of these materials, and the officinal salt of these materials and ester.

The example of anti-tussive agents and expectorant includes but not limited to: diphenhydramine, dextromethorphan, narcotine, chlophedianol, Menthol, benzonatate, ethylmorphine, codeine, acetylcysteine, S-Carbomethylcysteine, ambroxol, belladonna alkaloids, The pharmaceutically useful salt of sobrerol, guaiacol and guaifenesin, the isomer of these materials, and these materials and Prodrug.

The example of muscle relaxant includes but not limited to: cyclobenzaprine and chlorzoxazone, metaxalone, orphenadrine and U.S. The pharmaceutically useful salt of Suo Bamo, the isomer of these materials, and these materials and prodrug.

Anti-depressant example includes but not limited to caffeine.

Ataractic example includes but not limited to sleeping pill, such as antihistaminic (such as diphenhydramine), eszopiclone And zolpidem, and the pharmaceutically useful salt of these materials and prodrug.

The example of appetite suppressant includes but not limited to phenylpropanolamine, phentermine and diethyl cathinone, and these things The pharmaceutically useful salt of matter and prodrug.

The example of anesthetis (such as, be used for treating throat pain) includes but not limited to dyclonine, benzocaine and pectin, And the pharmaceutically useful salt of these materials and prodrug.

The suitably example of statins includes but not limited to: atorvastatin, rosuvastatin, fluvastatin, Lip river Cut down pharmaceutically useful salt and the prodrug of statin, simvastatin, atorvastatin, pravastatin, and these materials.

In one embodiment, the pharmaceutically active agents being included in tablet is selected from: phenylephrine, dextromethorphan, Pseudoephedrine, acetaminophen, cetirizine, aspirin, nicotine, ranitidine, ibuprofen, ketoprofen, loperamide, Famotidine, calcium carbonate, Simethicone, chlorphenamine, methocarbamol, chlophedianol, ascorbic acid, pectin, dyclonine, benzene are helped Caine and menthol, and the pharmaceutically useful salt of these materials and prodrug.

As it has been described above, the pharmaceutically active agents of the present invention can be with pharmaceutically useful salt such as acid/anion salt or alkali formula/sun Presented in ion salt.Pharmaceutically useful acid/anion salt includes but not limited to: acetate, benzene sulfonate, benzoate, Bicarbonate, biatrate, bromide, Ca-EDTA, camsilate, carbonate, chloride, citrate, two hydrochloric acid Salt, edetate, ethanedisulphonate, Estolate, esilate, fumarate, gluceptate, Portugal Sugar lime, glutamate, Glu, α-hydroxyl acetyl amino phenyl arsenic acid, hexyl resorcin salt, Hai Baming, hydrobromate, hydrochlorate, hydroxyl naphthalene Hydrochlorate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, methanesulfonic acid Salt, MB, methyl nitrate, Methylsulfate, mucus hydrochlorate, naphthalene sulfonate, nitrate, embonate, pantothenic acid Salt, phosphate/diphosphate, Polygalacturonate, salicylate, stearate, basic acetate, succinate, sulphuric acid Salt, tannate, tartrate, teoclate, toluene fulfonate and triethiodide.Pharmaceutically useful alkali formula/cationic salts includes But be not limited to: aluminium salt, benzathine benzylpenicillin salt, calcium salt, chloroprocaine salt, choline salt, diethanolamine salt, ethylenediamine salt, lithium salts, Magnesium salt, meglumine salt, potassium salt, procaine salt, sodium salt and zinc salt.

As it has been described above, the pharmaceutically active agents of the present invention can exist with the prodrug forms of pharmaceutically active agents.Generally, before this type of Medicine is the functional derivatives of pharmaceutically active agents, and these functional derivatives are readily converted into required pharmaceutically active agents in vivo.With In selecting and preparing " the Design of that the normal process steps of suitable prodrug derivant is edited at such as H.Bundgaard Prodrugs " described in (Elsevier, 1985).Outside desalination, the present invention also provides for the ester of described compound, amide, and Other shielded forms or derivative form.

If at least chiral centre of the pharmaceutically active agents according to the present invention, then they can be correspondingly as enantiomer Exist.If pharmaceutically active agents has two or more chiral centres, then they are alternatively arranged as diastereomer existence.Should manage Solving, all such isomer and mixture thereof are all contained within the scope of the present invention.Additionally, some crystal of pharmaceutically active agents Form can exist as polymorph, and this type of polymorph is equally directed to be included within the scope of the invention.It addition, some drugs Activating agent can form solvate (such as hydrate) with water or form solvate with ordinary organic solvents, and these solvates are also It is intended to be covered in the scope of the present invention.

In one embodiment, one or more pharmaceutically active agents are present in tablet with therapeutically effective amount, Qi Zhongzhi Treat effective dose be oral after can produce needed for the amount of therapeutic response, can easily be determined by those skilled in the art.Control determining When treating effective dose, as it is known in the art, must take into concrete pharmaceutically active agents, the bioavailability of pharmaceutically active agents used Characteristic, dosage regimen, the age of patient and body weight, and other factors.

Pharmaceutically active agents can exist in a variety of manners.Such as, pharmaceutically active agents can divide in tablet on a molecular scale Dissipating (as melted), can be maybe particulate forms, particle then can be coated, also can not be coated.If pharmaceutically active agents is grain Sub-form, the particle mean size of particle (in spite of being coated) is typically about 1 micron to about 500 microns.An embodiment In, this kind of particle is the crystal of the particle mean size with about 1 micron to about 300 microns.

Before adding taste masking coating, pharmaceutically active agents can exist with pure crystal form, or exists in granular form.Can make Flow behavior or the granularity of pharmaceutically active agents is improved, so that it is more suitable for follow-up coating operations with granulation technique.It is applicable to system Grain binding agent include but not limited to starch, polyvinyl pyrrolidone, polymethacrylates, hydroxypropyl methyl cellulose and Hydroxypropyl cellulose.The particle comprising pharmaceutically active agents can be with any method of granulating known in the art, by by pharmaceutically active Agent is jointly pelletized with suitable substrate particle and is formed.The example of this method of granulating includes but not limited to high shear wet granulation And fluidized bed granulation, such as rotating fluidized bed is pelletized.

If as it is known in the art, the taste of pharmaceutically active agents is unhappy, then can use taste masking coating packaging medicine activity Agent.Suitably the example of taste masking coating is in United States Patent (USP) No.4,851,226, United States Patent (USP) No.5,075,114 and United States Patent (USP) No.5,489,436 is described.May be used without the commercially available pharmaceutically active agents processed through taste masking.Such as, by coacervation second The acetaminophen particle of base cellulose or other polymeric encapsulates can be used for the present invention.The acetaminophen of cohesion encapsulating Can be from EurandAmerica, Inc. (Vandalia, Ohio) is commercially available.

In one embodiment, tablet releases coated bead (such as, the grain containing at least one pharmaceutically active agents mixed with tune Son, these particles represent the tune of this pharmaceutically active agents and release characteristic)." tune is released " used herein, should apply to refer to that activating agent exists Release or Dissolution behaviours in dissolution medium (such as gastro-intestinal Fluid) change.The type released is adjusted to include but not limited to slow release or slowbreak. Generally, be configured to modified release tablet formulations to make activating agent after picked-up long-time in all can be utilized, whereby with phase in conventional tablet Compared with the administration situation of activating agent, administration frequency reduces.Modified release tablet formulations also allows for using the combination of activating agent, one of which medicine The time of thing activating agent sustained effectiveness may differ from the time of another kind of pharmaceutically active agents sustained effectiveness.An embodiment In, this tablet contains a kind of i.e. to release the pharmaceutically active agents that mode discharges, and with modified release manner release other activating agent or The Part II being made up of the activating agent identical with the first activating agent.

It is used as the example bag at the swellability erodable water wetted material adjusting the excipient releasing the regulation release used in coating Include: water swellable cellulose derivant, poly alkylene glycol, thermoplastic polyalkylene oxides, acrylate copolymer, aqueous colloidal, viscous Soil and gelatinized starch.The example of the cellulose derivative of water-swellable includes: sodium carboxymethyl cellulose, cross-linked hydroxypropyl base fiber Element, hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), hydroxyl isopropyl cellulose, hydroxybutyl cellulose, oxybenzene Base cellulose, hydroxyethyl cellulose (HEC), hydroxyl amyl cellulose, Cellulose ethyl hydroxypropyl ether, hydroxypropyl butylcellulose and hydroxyl Ethyl cellulose.The example of poly alkylene glycol includes Polyethylene Glycol.The suitably example of thermoplastic polyalkylene oxides includes Poly(ethylene oxide).The example of acrylic polymer includes methacrylic acid potassium-divinyl benzene copolymer, polymethylacrylic acid Methyl ester, and the cross-linked acrylic acid homopolymer of high molecular and copolymer.

It is suitable for use as the pH dependent polymers adjusting the excipient releasing the regulation release used in coating to include: enteric solubility Cellulose derivative, as hydroxypropylmethyl cellulose phthalate, Hydroxypropyl Methyl Cellulose Phthalate and acetic acid are fine Dimension element phthalic acid ester；Natural resin, such as lac and zein；Enteric solubility acetate derivative, such as polyvinyl acetate neighbour's benzene Dicarboxylic acid esters, cellulose acetate phthalate and acetaldehyde dimethylcellulose acetate；With enteric acrylate's ester derivant, As polymethacrylates based polyalcohol, such as poly-(methacrylic acid, methyl methacrylate) 1:2 (can be with trade names EUDRAGIT S derives from Rohm Pharma GmbH) and poly-(methacrylic acid, methyl methacrylate) 1:1 (can be with trade name EUDRAGIT L derives from Rohm Pharma GmbH).

In one embodiment, pharmaceutically active agents with water-insoluble film forming polymer (such as, but not limited to acetate fiber Element or ethyl cellulose) and water-soluble polymer (such as, but not limited to polyvidone, polymethacrylic acid copolymer (such as Rohm America sell with trade name Eudragit E-100 those) and hydroxypropyl cellulose) combination carry out coating.Real at this Executing in scheme, water-insoluble film forming polymer is that insoluble polymer accounts for about 50% to about with the ratio of water-soluble polymer 95%, and water-soluble polymer accounts for about 5% to about 50%, and based on the weight of taste masking coated bead, the weight percent of coating Ratio about 5% to about 40%.

In one embodiment, the part of one or more pharmaceutically active agents or this pharmaceutically active agents can be bound to Ion exchange resin, to carry out taste masking or to deliver this pharmaceutically active agents with modified release manner to pharmaceutically active agents.

In one embodiment, pharmaceutically active agents can be molten when contacting the fluid of such as water, gastric acid, intestinal juice or the like Go out.In one embodiment, the dissolution characteristic of the tablet of drug containing activating agent meets the USP concrete regulation to rapid release.Such as, For Actamin Extra, USP 24 specifies, in pH 5.8 phosphate buffer, uses USP device 2 (oar with 50rpm Formula), acetaminophen contained in tablet in 30 minutes upon administration has at least 80% to discharge from this tablet, for ibuprofen Tablet, USP 24 specifies, in pH 7.2 phosphate buffer, with 50rpm use USP device 2 (paddle), 60 points upon administration Ibuprofen contained in tablet in clock has at least 80% to discharge from this tablet.See USP 24 (version in 2000) the 19-20 page and Page 856 (1999).In another embodiment, the dissolution characteristic of pharmaceutically active agents is regulated: such as controlled release, slow release, Extended release, resistance are released, long-acting, slowbreak etc..

In one embodiment, pharmaceutically active agents is included in particle (such as, the taste masking coated bead of polymer coating And/or sustained release coating particle) in.In one embodiment, first with taste masking coating coating active composition, then it is situated between with the second layer Electricity coating parcel.In one embodiment, pharmaceutically active agents is contained in base material and/or the coating of lossy coated bead Among Ceng.

In one embodiment, powder blend/tablet comprises the pharmaceutically active of about 10 weight % to about 40 weight % Agent, such as based on the weight of tablet/powder blend 15% to about 35%, such as based on the weight of tablet/powder blend 20% to about 30%.

As it has been described above, in one embodiment, pharmaceutically active agents is positioned at or is contained in lossy coated bead Within base material.In one embodiment, the amount of this kind of coated bead of drug containing activating agent can be by tablet/powder blend Weight meter about 10% to about 95%, such as based on the weight of tablet/powder blend 15% to about 70%, such as press tablet/ The level of the weight meter 20% to about 50% of powder blend exists.

In one embodiment, within pharmaceutically active agents is included in lossy coated bead.An embodiment In, first with the taste masking coating coating active composition without activator, then wrap up with the second layer coating containing activator.At one In embodiment, active component is added in the exterior coating containing activator.

Form tablet base

In one embodiment, in order to obtain the required attribute of oral cavity disintegration tablet, the structure of tablet can be that height is many Hole, and/or there is low-density (such as, so that tablet can be at intraoral disintegration).In a preferred embodiment, Expect by minimum power of tamping or do not use the power of tamping, so that it may realizing Orally disintegrating characteristic.

In one embodiment, tamp step (carrying out before applying radio-frequency (RF) energy) to apply to the cavity keeping material Power, with the air removed between particle in void space, enables material molding.In one embodiment, the power of applying is little In about 450 pounds/square inch (such as, less than about 300 pounds/square inch, all such as less than 200 pounds/square inch, all such as less than 50 pounds/square inch), it is upper in case material deforms further that this power rests on framework (or machinery " block piece "), thus does not applies Radio-frequency (RF) energy would not form tablet.In one embodiment, (machinery is not used in powder blend by this power effect Block piece) while apply radio-frequency (RF) energy.

In one embodiment, tamping step and carry out in indexing (indexed) mode, one of which tablet accepts simultaneously Process, then rotate to another indexing (indexing) station.In one embodiment, step is tamped at single turnover station Carry out, and apply energy and carry out at separate turnover station.In another embodiment, exist in which and carry out tablet or multi-disc The 3rd turnover station that tablet ejects, wherein descends forming tool to rise and rises to the surface of punch die.In another embodiment In, tamp step and carry out by air pressure or hydraulic cylinder being added to the top of upper forming tool.In one embodiment, simultaneously Ejecting multiple tablet, then with deflecting from rod (take-off bar), by multiple tablets, from the surface of this turnover station, separation moves then Remove.

In another embodiment, can use the method described in U.S. Patent Application Publication No.20040156902 and Equipment prepares tablet base.Specifically, the available individual equipment with double row die structure include fill area, insert district, The rotary compression module of blanketed zone, ejection district and clear (area) prepares tablet base.Then this pressing die can be filled by vacuum The punch die of block, among each punch die or near be both provided with filter.The clear (area) of compression module includes optional admixture of powder Thing recovery system, to reclaim unnecessary powder blend from filter and to send powder blend back to punch die.

In one embodiment, using United States Patent (USP) No.6 announced, the method and apparatus described in 767,200 comes Prepare tablet base.Specifically, the available individual equipment with double row die structure as shown in this paper Fig. 6 includes filling District, blanketed zone, the rotary compression module in ejection district prepare tablet.Preferably by vacuum, the punch die of compression module is filled out Fill, among each punch die or near be both provided with filter.

Tablet base can have the one of which in multiple difformity.Such as, tablet base can be configured to polyhedron, as vertical Cube, vertebral body, prism etc.；Or can have the geometry of the spatial shape with some non-planar surface, such as cone, cut Head cone, triangle, cylinder, spheroid, torus etc..In certain embodiments, tablet base has one or more master Surface.Such as, tablet base surface is generally of the phase formed by contacting with upper and lower forming tool surface (such as die-punch) To upper and lower surface.In this kind of embodiment, tablet base surface the most also include being positioned at upper surface and lower surface it Between " bellyband ", it is formed by contacting with die wall.Tablet base/tablet can also is that multilayer tablet base/tablet.Applicant It has been found that the sharpened edge in the mould preparing tablet may result in the starting the arc, thus more round edge may be needed.

Use vibrating step in one embodiment (such as, after powder filler blend but in heating or melted This step is added, to remove the air in powder blend) before step.In one embodiment, add frequency and be about 1Hz To the vibration of about 50KHz, the amplitude of peak to peak be 1 micron to 5mm, allow flowable powder blend deposit to punch die platen In chamber (" forming cavity ").

Radio-frequency (RF) energy is applied to powder blend

Described method includes applying the radio-frequency (RF) energy sufficiently long time to form this step of above-mentioned tablet to powder blend Suddenly.Although being not intended to bound to any specific theory, it is believed that activator is combined on the surface of passivator (base material) in advance makes table The conductivity in face is higher, so more direct path energizing quantity can be provided to pass through.This heating can be dielectric heating (such as, Use containing vinyl, ester, amide and/or the lossy polymer of carbamate-functional) or Ion Heating.Ion is added For heat, when blended thing is flowed on the surface of lossy coated bead in field, the moisture being trapped in powder blend can be to have The coating of loss provides storage energy source (such as, under 27MHz, pure water has high-k).Higher polymer/work is lost Agent can be efficiently used the energy of moisture storage and carrys out soft polymer chain and make polymer chain flow, thus passes through polymer chain Tangle and form secondary or physical bond.The key that the synergism provided by the configuration of lossy coated bead even can provide sufficiently large is strong Degree, enables the material not providing conducting path (or comprising lossy material) to be mixed into lossy coated bead, at this Filler is served as in bright.

Radio frequency heating is often referred to be about the electromagnetic field heating of 1MHz to about 100MHz by frequency.An enforcement in the present invention In scheme, radio-frequency (RF) energy is about 1MHz to about 100MHz in frequency, and (e.g., from about 5MHz to 50MHz, all such as from about 10MHz are to about In the range of 30MHz).In one embodiment, radio-frequency (RF) energy is used to heat the first material.Radio frequency energy generator is this Known to field.The suitably example of radio-frequency signal generator includes but not limited to self-excited oscillator, such as COSMOSC10X16G4 type (Cosmos Electronic Machine Corporation, Farmingdale, NY) or 50 Ohm radio frequency generators.One In individual embodiment, radio-frequency (RF) energy being combined with Secondary Heat Source, wherein Secondary Heat Source includes but not limited to infrared heating, sensing Heating or Convective Heating.

In this embodiment, electrode is merged in and keeps the room of powder blend (such as cylindrical chamber, the room that surrounds with wallboard Or other rooms) in.In one embodiment, described room is formed by conducting metal structure.In one embodiment, described room Have by the some of non-conductive insulation construction.In one embodiment, described room has non-conductive Plug-in unit, but the main body of room is conduction.In one embodiment, the surface area of described plug-in unit is less than the surface area of room.Conduction Material can be by the material (include but not limited to aluminum, copper, ferrum, zinc, nickel, and the mixture of these materials and alloy) of any conduction Composition.Non-conducting material can be by non-conductive solid material (including but not limited to pottery, polystyrene and politef) group Become.In one embodiment, cylindrical chamber or the room that surrounds with wallboard have at least one and embed the electrode in its wall.This electricity Pole can be surrounded by non-conducting material, and wherein electrode is exposed to the unique conductive wall part of powder blend.An embodiment party In case, first tamp powder blend, then apply radio-frequency (RF) energy.

In one embodiment, a room accommodates powder blend, and then this room is placed in other room (such as baking oven) In to apply energy.In another embodiment, the other heating unit during the room equipped with powder blend has and enters the room Part.

After applying energy, the most first cool down powder blend (such as, force cooling or make its natural cooling), then The powder blend applying energy allowing scheduled volume forms tablet.

Can be used for the example applying the equipment of this energy at U.S. Patent application No.20110068511 and Shown in No.20130295211.

Multilayer tablet

In certain embodiments, tablet includes at least two-layer, such as, have dissimilar and/or the first of concentration or At least two-layer of the pharmaceutically active agents of the second material and/or other compositions or variable concentrations.In one embodiment, tablet bag Including two-layer, one layer has Orally disintegrating character, and another layer is masticable or deglutible.In one embodiment, one layer Tamp with higher compaction force relative to another layer.In one embodiment, two-layer have different amounts of pharmaceutically active agents and/ Or other excipient.In one embodiment, all character of two-layer are the most identical, but the color of two-layer is different.A reality Executing in scheme, not all layer all comprises coated bead (such as, only having a layer in two-layer to comprise).An embodiment In, the two-layer of dosage form all comprises coated bead, but the composition of coated bead (such as, constitutes the material of coated bead and/or described The relative quantity of material) different.

Effervescent antithesis thing

In one embodiment, powder blend/tablet is possibly together with one or more effervescent antithesis things.An enforcement In scheme, a member of effervescent antithesis thing is selected from sodium bicarbonate, potassium bicarbonate, calcium carbonate, magnesium carbonate and sodium carbonate, another Member is selected from citric acid, malic acid, fumaric acid, tartaric acid, phosphoric acid and alginic acid.

In one embodiment, effervescent antithesis thing merging amount in powder blend/tablet accounts for powder blend/sheet About 2 weight % of agent gross weight are to about 20 weight %, and all such as from about 2 weight % are to about 10 weight %.

Oral cavity disintegration tablet

In one embodiment, during by tablet design for being placed on tongue, (such as it is shorter than about 45 being shorter than about 60 seconds Second, be such as shorter than about 30 seconds, such as, be shorter than about 15 seconds) time at intra-oral disintegration.

In one embodiment, tablet meets " food and the drug control draft guidelines " announced in April, 2007 The standard of oral cavity disintegration tablet (ODT) defined in (draft Food and Drug Administration guidance). In one embodiment, described tablet meets the dual definition to oral cavity disintegration tablet, including following standard: 1) solid tablet Comprise medical substance, and can quickly (generally in several seconds) disintegrate when being placed on tongue；With 2) it is considered in oral cavity Quickly disintegrated solid orally ingestible, its with according to American Pharmacopeia (USP 24NF 29) for one or more particular drug things When the disintegrate method of testing of matter is tested, disintegration time in vitro was about 30 seconds or less than 30 seconds.

Tablet coating

In one embodiment, tablet comprises other outer coatings (such as translucent coating, the most colourless coating), is used for Give the characteristic that dosage form is other.The suitable material of this coating includes but not limited to: hypromellose, hydroxypropyl cellulose, The mixture of starch, polyvinyl alcohol, Polyethylene Glycol, polyvinyl alcohol and Polyethylene Glycol and copolymer, and the mixing of these materials Thing.The tablet of the present invention can comprise by tablet total weight gauge about 0.05% to about 10% or the coating of about 0.1% to about 5%.

The hardness of tablet, friability and density

In one embodiment, prepare tablet make that this tablet is relatively soft (such as, can disintegrate or can nozzle in mouth Chew).Hardness test (resistance to compression hardness) is based on the model 6d being perpendicular to use amendment at cross section bellyband, is furnished with 50g power and bears The dosage form measured by Pharmatron hardness-testing device of lotus sensor (for test the lower power needed for the present invention) hard Degree.Except as otherwise noted, otherwise test is carried out on two lamination tablets, and hardness is reported as measured hardness 50%.In one embodiment, the hardness of tablet is less than 1 kilogram, all such as less than 0.5 kilograms.

In one embodiment, the density of tablet is at least about 0.6g/cc.In one embodiment, tablet is close Degree less than about 1.5g/cc.In one embodiment, the bulk density of lossy coated bead is about 0.5g/cc to about 1g/ cc。

In one embodiment, the friability of tablet is less than 10%, all such as less than 5%, all such as less than 3%.Herein " friability " used uses USP 24NF 29 tablet friability (the 1216th part) to measure after following amendment: make Carry out 15 turns with 3 tablets or 3 tablets carry out 100 revolutions (unless otherwise noted) rather than 10 tablets carry out 100 turns.

The purposes of tablet

Can be used as to swallow matrix agent, masticatory pattern tablet or Orally disintegrating matrix agent to use pharmaceutically active agents by tablet.

In one embodiment, the method that the present invention relates to treat disease, the method includes oral above-mentioned tablet, wherein This tablet comprises a certain amount of pharmaceutically active agents that can effectively treat this disease.The example of this type of disease includes but not limited to: pain Bitterly (such as headache, migraine, throat pain, angor, backache and myalgia), fever, inflammation, upper respiratory tract obstacle (such as cough and Congested), infect (such as antibacterial and virus infect), depression, diabetes, obesity, cardiovascular disorder (such as hypercholesterolemia, High triglyceride and hypertension), gastrointestinal disorders (such as feel sick, dysentery, irritable bowel syndrome and flatulence), sleep disorder, bone Matter is loosened and nicotine dependence.

In one embodiment, the method is used for treating upper respiratory tract obstacle, and wherein pharmaceutically active agents is selected from: deoxygenate kidney Upper parathyrine, cetirizine, loratadine, fexofenadine, diphenhydramine, dextromethorphan, chlorphenamine, chlophedianol and puppet fiber crops Yellow alkali.

In this embodiment, " unit dose " generally illustrates with administration, and this explanation instructs patient to be somebody's turn to do according to (such as) The age of patient or body weight take a certain amount of pharmaceutically active agents, and this amount can be multiple this unit dose.Generally, unit dose Measure volume by containing the pharmaceutically active agents effectively measured in treatment for minimum patient.Such as, suitable unit dose Volume can include one tablet.

Embodiment

Specific embodiments of the present invention are shown by following example.The present invention is not limited in these embodiments The concrete restriction illustrated.

Embodiment 1: prepare mannitol particle and the tablet of gained of hydroxypropyl cellulose (HPC) coating

Part A: produce lossy coated bead: prepare the HPC coating mannitol grain of a collection of 14kg by following operation Son.Then use these lossy coated bead to produce the oral cavity disintegration tablet of part B.

Lossy Coating Solution:

1. USP level purified water is added in the rustless steel container that size is suitable.

2. (" HPC ", with trade name to add hydroxypropyl celluloseEF is from Ashland Specialty Ingredients buys) as activator, limit edged is gently mixed, and obtains the solution that solid concentration is 4%.

Use lossy Coating Solution parcel substrate particle (as passivator):

1. take 14000g mannitol (as base material) and add Aeromatic S2 (GEA Group) top-jet-type fluid bed system In grain machine.

2. the Coating Solution that would detract from consumption is sprayed onto on mannitol with the spray rate of 50 gram/minute, until concentration reaches To 0.6 weight %, based on dry loss, aqueous percentage ratio is 10.4%.

3. coated bead is further dried, until aqueous percentage ratio is about 0.38% based on dry loss.

Part B: use HPC coated bead preparation tablet: use the machine disclosed in United States Patent (USP) No.20130295211, The lossy coated bead that part A produces is filled in 12.5mm circular die, sinters 0.8 second with the radio frequency of about 27MHz (" sintering time " is 0.8 second), forms oral cavity disintegration tablet.Regulation electrode distance and variable condenser, remove in void space Air, optimize adjustment oscillation circuit simultaneously, make abundant energy be displaced through material and form tablet, and do not cause electric arc to put Electricity or phosphere.The information relevant with gained tablet is shown in table 4 to table 7.

Comparative example 2: there is the activator of the dry-blend being made into separate particle and the preparation of the tablet of passivator

Produce tablet with this comparative example to illustrate that by HPC coating mannitol particle manufacture (as described in Example 1) Tablet and use HPC particle (activator) and maltose alcohol particle (passivator) dry-blend manufacture tablet between difference Different.The blend of HPC particle Yu maltose alcohol particle is put into the polystyrene containers of rigid seal, is placed in It is blended five minutes in blender (Impandex, Inc.Maywood, NJ).Result is recorded in table 2B.

Table 2B

* DT disintegration time

1: the disintegration time recorded according to the disintegration of tablet method of testing of American Pharmacopeia USP 24

N/a is inapplicable

For the HPC dry-blend less than 10 w/w %, gained tablet is the most frangible and is difficult to process.Just with 15 to For the dry-blend that 20 w/w %HPC prepare, gained tablet can use radio-frequency (RF) energy sintering to shape therewith, but obtained sheet Agent is the most extremely fragile.For the tablet of 22%HPC, gained tablet has qualified friability (3.1%), but disintegration time surpasses Spending 30 seconds, this is worthless for oral cavity disintegration tablet, and is unsatisfactory for USP requirement.Modification time, tamp and the system such as adjustment Make setting and do not overcome produced long disintegration time, therefore show with activator parcel passivator particle rather than only will activate Agent and passivator are blended as separate particle, and there are unexpected benefits for tool.

Embodiment 3: prepare the mannitol particle of hydroxyethyl cellulose (HEC) coating

Part A: produce lossy coated bead: the HEC coating mannitol grain of a collection of 14kg is prepared by following operation Son.Then these lossy coated bead are used to carry out the oral cavity disintegration tablet of part B in production example 3.

Lossy Coating Solution:

1. USP level purified water is added in the rustless steel container that size is suitable.

2. add hydroxyethyl cellulose (with trade name Natrosol 250 from Ashland Specialty Ingredients buys) as activator, limit edged is gently mixed, and obtains the solution that solid concentration is 4%.

Lossy Coating Solution is used to wrap up substrate particle:

3. take 14000g mannitol (as base material) to add in top-jet-type fluidised bed granulator.

4. the Coating Solution that would detract from consumption is sprayed onto on mannitol with the spray rate of 50 gram/minute, until concentration reaches To 0.5 weight %, based on dry loss, aqueous percentage ratio is 2.7%.

5. granule is further dried, until aqueous percentage ratio is about 0.18% based on dry loss.

Part B: use hydroxyethyl cellulose coated bead to prepare tablet with acetaminophen: raw by the formula in table 3 Produce the tablet of weight 566mg.Use the method described in embodiment 1, blend is filled in 12.5mm circular die, with 27MHz Radio frequency sinters about 0.8 second, forms oral cavity disintegration tablet.The disintegration time recorded by USP 24 is shorter than 30 seconds, and the friability of tablet Degree is less than 3% (taking 3 tablets, fall 15 times respectively).

Table 3

1: with trade name acetaminophenPurchased from Aptalis company

Embodiment 4: change lossy coating amount and type of substrate

It is prepared for many batches of lossy coated bead, is then prepared for adding the tablet of pharmaceutically active agents further and not entering One step adds the tablet of pharmaceutically active agents.About the information of these batch of materials described in the table 4 below to table 7.Carry out chewing (external) Gustation is tested, and uses American Pharmacopeia disintegration of tablet to test (USP 24), records disintegration time.For table 4 to table 7: (i) is right Rotation sugar adds with Dextrose monohydrous form；(ii) PE refers to phenylephrine hydrochloride；(iii) DPH refers to diphenhydramine；APAP Refer to acetaminophen；N/A refers to unavailable.The method of computational geometry average diameter is directed to use with to purchase from Sepor company The ATM audio frequency sieve obtained carries out sieve analysis.Take about 10g material ATM audio frequency sieve and perform sieve analysis.As an alternative, for The sample that granularity is bigger, uses and can sieve from the FMC sieve shaker that FMC Corp. buys.Take about 100g material FMC reciprocating gird Machine performs analysis.

Embodiment 4A: according to the operation described in embodiment 1, utilize 0.5 weight % hydroxypropyl cellulose (EF) Prepare lossy coated bead.In the Coating Solution for mannitol coating, add phenylephrine, make final product form In reach 12.1mg dosage level.The tablet of preparation tablet weight 169mg, then sintering 1.5 seconds.

Embodiment 4B: utilize the operation described in embodiment 1 to prepare lossy coated bead, wherein replace with erythritol Mannitol is as base material.The content of hydroxypropyl cellulose (activator) is increased to 0.7 weight %.The sheet of preparation tablet weight 486mg Agent, then sintering 0.8 second.

Embodiment 4C: the coating erythritol particle that Example 4B prepares, with the diphhydramine hydrochloride of coating (dosage of 40.5mg/ sheet) is blended.Prepare the tablet of 482mg, then sintering 1.5 seconds.

Embodiment 4D: extra addition 0.17 weight % in the Coating Solution that hydroxypropyl cellulose concentration is 0.5 weight % Sodium chloride, prepare coating mannitol particle according to the operation described in embodiment 1.The tablet of preparation tablet weight 383mg, then burns Tie 1.0 seconds.

Embodiment 4E: use the operation described in embodiment 1 to prepare lossy coated bead, but replace with Dextrose monohydrous Mannitol is as base material.Hydroxypropyl cellulose is added with the level of 0.5 weight %.Preparation weight is the tablet of 532mg, then Sinter 1.0 seconds.

Embodiment 4F: utilize the operation described in embodiment 1 to prepare lossy coating mannitol particle, but by hydroxypropyl The content of cellulose increases to 0.8% (based on the weight of coating mannitol).It is not added with the situation of active component in the blend Under, preparation tablet weight is the tablet of 397mg, then sintering 0.5 second.

Embodiment 4G: utilize the operation described in embodiment 1 to prepare lossy coating mannitol particle, but by hydroxypropyl The content of cellulose increases to 0.9% (based on the weight of coating mannitol).It is not added with the situation of active component in the blend Under, preparation tablet weight is the tablet of 397mg, then sintering 0.5 second.

Embodiment 4H: utilize the operation described in embodiment 1 to prepare lossy coating mannitol particle, but by hydroxypropyl The content of cellulose increases to 0.9% (based on the weight of coating mannitol).Then by coating mannitol and 10 weight % Erythritol powders is blended.In the case of being not added with active component in the blend, preparation tablet weight is the tablet of 407mg, then Sinter 0.5 second.

Embodiment 4I: utilize the operation described in embodiment 1 to prepare lossy coating mannitol particle, but by hydroxypropyl The content of cellulose increases to 0.9% (based on the weight of coating mannitol).Then by coating mannitol and encapsulating to second Acylamino-phenol (37mg dosage) is blended.In the case of being not added with active component in the blend, preparation tablet weight is the sheet of 416mg Agent, then sintering 1.0 seconds.

Embodiment 4J: utilize the operation described in embodiment 4I, use 0.9% (based on the weight of coating mannitol) relatively low (about 40,000 dalton, with trade name for the other hydroxypropyl cellulose of molecular levelSSL is purchased from Nippon Soda Co.) lossy coated bead is prepared.In the case of being not added with active component in the blend, preparation tablet weight is the sheet of 389mg Agent, then sintering 0.5 second.

Embodiment 4K: use the operation described in embodiment 1 to prepare lossy coated bead, but replace sweet with maltose alcohol Dew sugar alcohol is as base material.Maltose alcohol is used as the example of moisture absorption sugar.Level (based on the weight of coating maltose alcohol) by 0.9% Add hydroxypropyl cellulose.Preparation weight is the tablet of 661mg, then sintering 1.0 seconds.

Embodiment 4L: use the operation described in embodiment 1 to prepare lossy coated bead, but replace sweet with maltose alcohol Dew sugar alcohol is as base material, and the content that hydroxypropyl cellulose is in coating maltose alcohol is 0.9%.(press with the level of 0.18% The weight meter of coating maltose alcohol) in Coating Solution, add glyceryl monostearate (GMS), as helping of coating maltose alcohol Agent.In the case of being not added with active component in the blend, preparation tablet weight is the tablet of 578mg, then sintering 0.5 second.

Embodiment 4M: use the operation described in embodiment 1 to prepare lossy coated bead, but replace sweet with maltose alcohol Dew sugar alcohol is as base material.Level (based on the weight of coating maltose alcohol) by 0.9% adds hydroxypropyl cellulose.Preparation weight For the tablet of 631mg, then sintering 1.5 seconds.

Embodiment 4N: use the operation described in embodiment 1 to prepare lossy coated bead, but replace sweet with maltose alcohol Dew sugar alcohol is as base material.Level (based on the weight of coating maltose alcohol) by 0.9% adds hydroxypropyl cellulose.Then with 155mg dosage adds the acetaminophen of encapsulating.Prepare the tablet of 609mg, then sintering 1.5 seconds.

Embodiment 4O: use the operation described in embodiment 1 to prepare lossy coated bead, but replace sweet with maltose alcohol Dew sugar alcohol is as base material.Level (based on the weight of coating maltose alcohol) by 0.9% adds hydroxypropyl cellulose.Then with 160mg dosage adds the acetaminophen of encapsulating.Preparation weight is the tablet of 625mg, then sintering 1.5 seconds.

Embodiment 4P: use the operation described in embodiment 1 to prepare lossy coated bead, but replace sweet with maltose alcohol Dew sugar alcohol is as base material.Level (based on the weight of coating mannitol) by 1.2% adds hydroxypropyl cellulose.Preparation weight For the tablet of 546mg, then sintering 1.5 seconds.

Embodiment 4Q: utilize the operation described in embodiment 1 to prepare lossy coated bead, but the containing of hydroxypropyl cellulose Amount is 1.2% (based on the weight of coating mannitol).Then the acetaminophen of encapsulating is added with 160mg dosage.Preparation The tablet of tablet weight 694mg, then sintering 1.5 seconds.The Orally disintegrating time of these tablets is 32 seconds.

Embodiment 4R: utilize the operation described in embodiment 1 to prepare lossy coated bead, but the containing of hydroxypropyl cellulose Amount is 1.0% (based on the weight of coating mannitol).Then the acetaminophen of encapsulating is added with 325mg dosage.Preparation The tablet of tablet weight 807mg, then sintering 0.5 second.

Embodiment 4S: utilize the operation described in embodiment 1 to prepare lossy coated bead, but by hydroxypropyl cellulose Content is down to 0.4% (based on the weight of coating mannitol).Then the acetaminophen of encapsulating is added with 137mg dosage. The tablet of preparation tablet weight 509mg, then sintering 0.5 second.

Embodiment 4T: utilize the operation described in embodiment 1 to prepare lossy coated bead, but by hydroxypropyl cellulose Content is down to 0.4% (based on the weight of coating mannitol).Then the acetaminophen of encapsulating is added with 128mg dosage. The tablet of preparation tablet weight 475mg, then sintering 0.5 second.Fall 15 times time, the friability of these tablets be more than 2.0% (3.9%).

Table 4

Table 5

Table 6

Table 7

Embodiment 5: use daltonian 1% hydroxypropyl cellulose of molecular weight 80,000 to produce lossy coated bead

A collection of 6.1kg lossy coating maltose alcohol particle is prepared by following operation.Use slotted line measurement method dielectric Characterize lossy coated bead, by result record in table 8A.Then use these lossy coated bead to produce reality Execute the oral cavity disintegration tablet (table 8A and table 8B) in example 5A to 5G.

Lossy Coating Solution:

1. USP level purified water is added in the rustless steel container that size is suitable.

2. add 60g hydroxypropyl cellulose (with trade nameEF is from Ashland SpecialtyIngredients buys) as activator, limit edged is gently mixed, and obtains the solution that solid concentration is 4%.

Use hydroxypropyl cellulose Coating Solution parcel substrate particle:

3. take 6000g maltose alcohol to add in top-jet-type fluidised bed granulator.

4. the Coating Solution that would detract from consumption is sprayed onto on mannitol with the average spray rate of about 115 gram/minute, prepares The lossy coated bead of 1.0 w/w %, the target aqueous hundred at the end of making up to the sprinkling as pointed by table 8A Proportion by subtraction (based on dry loss).

The most then lossy coated bead is further dried, makes up to the aqueous percentage ratio that table 8A is recorded.

Embodiment 5A to 5G: use 80,000 daltonian 1% hydroxypropyl celluloses to produce lossy as activator Coated bead

According to the operation described in embodiment 5, the hydroxypropyl cellulose of 1.0% rate of body weight gain is utilized to prepare lossy coating grain Son.The coated bead that would detract from consumption is blended with coating APAP (90% titer), reaches the concentration of 20%, 30%, 40% or 50%, Make the tablet (seeing table 8A and table 8B) of 80mg, 160mg or 325mg acetaminophen dosage.

Table 8A

Table 8B

Embodiment 6: use daltonian 1% hydroxypropyl cellulose of molecular weight 40,000 to produce lossy coated bead

A collection of 6.1kg lossy coating maltose alcohol particle is prepared by following operation.Use slotted line measurement method dielectric Characterize lossy coated bead, by result record in table 8A.Then use these lossy coated bead to produce reality Execute the oral cavity disintegration tablet (table 9A and table 9B) in example 6A to 6G.

Lossy Coating Solution:

1. USP level purified water is added in the rustless steel container that size is suitable.

2. add 60g hydroxypropyl cellulose (with trade nameELF is from Ashland Specialty Ingredients buys) as activator, limit edged is gently mixed, and obtains the solution that solid concentration is 4%.

Use hydroxypropyl cellulose Coating Solution parcel substrate particle:

3. take 6000g maltose alcohol to add in top-jet-type fluidised bed granulator.

4. the Coating Solution that would detract from consumption is sprayed onto on mannitol with the average spray rate of about 103 gram/minute, prepares The lossy coated bead of 1.0 w/w %, the target aqueous hundred at the end of making up to the sprinkling as pointed by table 9A Proportion by subtraction (based on dry loss).

The most then lossy coated bead is further dried, makes up to the aqueous percentage ratio that table 9A is recorded.

Embodiment 6A to 6G: using daltonian 1% hydroxypropyl cellulose of molecular weight 40,000 to produce as activator has The coated bead of loss

According to the operation described in embodiment 6, the hydroxypropyl cellulose of 1.0% rate of body weight gain is utilized to prepare lossy coating grain Son.The coated bead that would detract from consumption is blended with coating APAP (90% titer), reaches the concentration of 20%, 30%, 40% or 50%, Make the tablet (seeing table 9A and table 9B) of 80mg, 160mg or 325mg acetaminophen dosage.

Table 9A

Table 9B

Embodiment 7: use daltonian 1% hydroxypropyl cellulose of molecular weight 140,000 to produce lossy coated bead:

A collection of 6.1kg lossy maltose alcohol particle is prepared by following operation.Use slotted line measurement method dielectric characterization Lossy coated bead, by result record in table 10A.Then these lossy coated bead are used to carry out production example Oral cavity disintegration tablet (table 10A and table 10B) in 7A to 7G.

Lossy Coating Solution:

1. USP level purified water is added in the rustless steel container that size is suitable.

2. add 60g hydroxypropyl cellulose (with trade nameJF is from Ashland Specialty Ingredients buys) as activator, limit edged is gently mixed, and obtains the solution that solid concentration is 4%.

Use hydroxypropyl cellulose Coating Solution parcel substrate particle:

3. take 6000g maltose alcohol to add in top-jet-type fluidised bed granulator.

4. the Coating Solution that would detract from consumption is sprayed onto on mannitol with the average spray rate of about 111 gram/minute, prepares The lossy coated bead of 1.0 w/w %, the target at the end of making up to the sprinkling as pointed by table 10A is aqueous Percentage ratio (based on dry loss).

The most then these particles are further dried, make up to the aqueous percentage ratio that table 10A is recorded.

Embodiment 7A to 7G: use 140,000 daltonian 1% hydroxypropyl celluloses to produce lossy as activator Coated bead:

According to the operation described in embodiment 7, the hydroxypropyl cellulose of 1.0% rate of body weight gain is utilized to prepare lossy coating grain Son.The coated bead that would detract from consumption is blended with coating APAP (90% titer), reaches the concentration of 20%, 30%, 40% or 50%, Make the tablet (seeing table 10A and table 10B) of 80mg, 160mg or 325mg acetaminophen dosage.

Table 10A

Table 10B

Embodiment 8: use 0.5% hydroxyethyl cellulose to produce lossy coated bead as activator

A collection of 6.1kg lossy coating maltose alcohol particle is prepared by following operation.Use slotted line measurement method dielectric Characterize lossy coated bead, by result record in table 11.Then use these lossy coated bead to produce reality Execute the oral cavity disintegration tablet (table 11) in example 8A to 8D.

Polymer coating solution:

1. USP level purified water is added in the rustless steel container that size is suitable.

2. add 60g hydroxyethyl cellulose (with trade name Natrosol 250L from Ashland Specialty Ingredients buys) as activator, limit edged is gently mixed, and obtains the solution that solid concentration is 2%.

Use hydroxyethyl cellulose Coating Solution parcel substrate particle:

3. take 6000g maltose alcohol to add in top-jet-type fluidised bed granulator.

4. polymer coating solution is sprayed onto on mannitol with the average spray rate of about 111 gram/minute, prepares The lossy coated bead of 0.5 w/w %, makes up to the target aqueous hundred at the end of spraying as noted in Table 11 Proportion by subtraction (based on dry loss).

The most then these particles are further dried, make up to the aqueous percentage ratio that table 11 is recorded.

Embodiment 8A to 8D: according to the operation described in embodiment 8, utilize the hydroxyethyl cellulose of 1.0% rate of body weight gain to prepare Lossy coated bead.The coated bead and the coating APAP (90% titer) that would detract from consumption are blended, reach 20%, 30%, The concentration of 40% or 50%, makes the tablet (seeing table 11) of 80mg, 160mg or 325mg acetaminophen dosage.

Table 11

Embodiment 9: use 1% hydroxyethyl cellulose to produce lossy coated bead as activator

A collection of 6.1kg lossy coating maltose alcohol particle is prepared by following operation.Use slotted line measurement method dielectric Characterize lossy coated bead, by result record in table 12.Then use these lossy coated bead to produce reality Execute the oral cavity disintegration tablet (table 12) in example 9A to 9D.

Lossy Coating Solution:

1. USP level purified water is added in the rustless steel container that size is suitable.

2. add 120g hydroxyethyl cellulose (with trade name Natrosol 250L from Ashland Specialty Ingredients buys) as activator, limit edged is gently mixed, and obtains the solution that solid concentration is 4%.

Use hydroxyethyl cellulose Coating Solution parcel substrate particle:

3. take 6000g maltose alcohol to add in top-jet-type fluidised bed granulator.

4. the Coating Solution that would detract from consumption is sprayed onto on mannitol with the average spray rate of about 111 gram/minute, prepares The lossy coated bead of 1.0 w/w %, makes up to the target aqueous hundred at the end of spraying as noted in Table 12 Proportion by subtraction.

The most then these particles are further dried, make up to the aqueous percentage ratio that table 12 is recorded.

Embodiment 9A to 9D: according to the operation described in embodiment 9, utilize the hydroxyethyl cellulose of 0.5% rate of body weight gain to prepare Lossy coated bead.The coated bead and the coating APAP (90% titer) that would detract from consumption are blended, reach 20%, 30%, The concentration of 40% or 50%, makes the tablet (seeing table 12) of 80mg, 160mg or 325mg acetaminophen dosage.

Table 12

Embodiment 10: use 2% hydroxypropyl cellulose to produce lossy coated bead as activator

A collection of 6.1kg lossy coating maltose alcohol particle is prepared by following operation.Use slotted line measurement method dielectric Characterize lossy coated bead, by result record in table 13.Then use these lossy coated bead to produce reality Execute the oral cavity disintegration tablet (table 13) in example 10A to 10D.

Lossy Coating Solution:

1. USP level purified water is added in the rustless steel container that size is suitable.

2. add 120g hydroxypropyl cellulose (with trade nameEF is from Ashland Specialty Ingredients buys) as activator, limit edged is gently mixed, and obtains the solution that solid concentration is 4%.

Use hydroxyethyl cellulose Coating Solution parcel substrate particle:

3. take 6000g maltose alcohol to add in top-jet-type fluidised bed granulator.

4. the Coating Solution that would detract from consumption is sprayed onto on mannitol with the average spray rate of about 110 gram/minute, prepares The lossy coated bead of 2 w/w %, makes up to the aqueous percentage of target at the end of spraying as noted in Table 13 Than (based on dry loss).

The most then it is dried these particles, makes up to the aqueous percentage ratio that table 13 is recorded.

Embodiment 10A to 10F: according to the operation described in embodiment 10, utilize the hydroxyethyl cellulose system of 1.0% rate of body weight gain Standby lossy coated bead.The coated bead and the coating APAP (90% titer) that would detract from consumption are blended, reach 20%, 30%, The concentration of 40% or 50%, makes the tablet (seeing table 13) of 80mg, 160mg or 325mg acetaminophen dosage.

Table 13

Embodiment 11: using 0 to 1% hydroxyethyl cellulose as activator, mixing sodium citrate and/or glycerol are as auxiliary Agent produces lossy coated bead

A collection of 6.1kg lossy coating maltose alcohol particle is prepared by following operation.Use slotted line measurement method dielectric Characterize lossy coated bead, by result record in table 14.Then use these lossy coated bead to produce reality Execute the oral cavity disintegration tablet (table 14A to table 14B) in example 11A to 11E.With the maltose alcohol being uncoated make sample 11F and 11G, as comparing with blend, thus proves the character of the tablet samples without coated bead.Un-sintered these compare with altogether Mixed thing forms tablet.

Lossy Coating Solution:

1. USP level purified water is added in the rustless steel container that size is suitable.

2. add 120g hydroxyethyl cellulose (with trade name250L buys) as activator, limit edged is light Light stirring, obtains the solution (about 25kg) that solid concentration is 2.5% to 4%.

Use hydroxyethyl cellulose Coating Solution parcel substrate particle:

3. take 6000g maltose alcohol to add in top-jet-type fluidised bed granulator.

4. the Coating Solution that would detract from consumption is sprayed onto on maltose alcohol with the average spray rate of about 110 gram/minute, prepares The lossy coated bead of 2 w/w %, makes up to the target at the end of table 14A to the sprinkling pointed by table 14B Aqueous percentage ratio (based on dry loss).

The most then it is dried these particles, makes up to the aqueous percentage ratio that table 14A to table 14B is recorded.

Embodiment 11,11A to 11E: according to the operation described in embodiment 11, utilize the hydroxy ethyl fiber of 1.0% rate of body weight gain Element prepares lossy coated bead.The coated bead and the coating APAP (90% titer) that would detract from consumption are blended, reach 20%, 30%, the concentration of 40% or 50%, make 80mg, 160mg or 325mg acetaminophen dosage tablet (see table 14A and Table 14B).

Table 14A

HEC: hydroxyethyl cellulose

Table 14B

HEC: hydroxyethyl cellulose

A: do not wrap up the particle of HEC

B: owing to these blends un-sintered form tablet, therefore cannot test

The e ' and e of test coated bead "

Embodiment 12: use different polymer to produce lossy coated bead as activator

Many batches of 6.1kg lossy coating maltose alcohol particles are prepared by following operation.Use slotted line measurement method dielectric Characterize lossy coated bead, by result record in table 15A and table 15B.Then these lossy coated bead are used Carry out the oral cavity disintegration tablet (table 15A and table 15B) in production example 12 and 12A to 12H.

Lossy Coating Solution:

1. USP level purified water is added in the rustless steel container that size is suitable.

2. add 120g polymer (as shown in table 15 below) to be gently mixed as activator, limit edged, obtain about 25kg The solution (depending on assessed polymer) that solid concentration is 2% to 5%.

Use polymer coating solution parcel substrate particle:

3. take 6000g maltose alcohol to add in top-jet-type fluidised bed granulator.

4. the Coating Solution that would detract from consumption is sprayed onto maltose alcohol with the average spray rate of about 100 to 110 gram/minute On, prepare the lossy coated bead of 1 w/w %, make up to the sprinkling as pointed by table 15A and table 15B and terminate Time the aqueous percentage ratio of target (based on dry loss).

The most then these particles it are dried.

Embodiment 12,12A to 12H: according to the operation described in embodiment 12, utilize the polymer of 1.0% rate of body weight gain to prepare Lossy coated bead.

Table 15A

The e ' and e of test coated bead "

1: with trade namePurchased from EMD Millipore company

2: with trade name KollicoatPurchased from BASF AG

3: with trade name KollicoatPurchased from BASF AG

4: with trade name KollicoatPurchased from BASF AG

Table 15B

The e ' and e of test coated bead "

5: with trade nameRS30D is purchased from Evonik company

6: with trade nameK12 is purchased from Ashland company

7: with trade namePurchased from BASF AG

8: with trade nameS630 is purchased from Ashland company

Embodiment 13: prepare the Eudragit RD30D coated bead that the acetaminophen with encapsulating is blended

Also the batch of material in above example 12D and 29% coating acetaminophen are blended, then burn by radio-frequency (RF) energy Knot generates tablet, as embodiment 12 is summarized.The various parameters of this kind of particle are as follows.

Table 16

1: be dried loss (weight % of water)

Embodiment 14: use different polymeric activators and the lossy coated bead of plasticizer production

Many batches of 6.1kg lossy coating maltose alcohol particles are prepared by following operation.Use slotted line measurement method dielectric Characterize lossy coated bead, by result record in table 17A.Then use these lossy coated bead to produce reality Execute the oral cavity disintegration tablet (table 17A to table 17B) in example 14A to 14H.

Lossy Coating Solution:

1. USP level purified water is added in the rustless steel container that size is suitable.

2. addition 120g polymer (as shown in following table) is as activator, and 47g plasticizer (activator and plasticizer Ratio be 72:24), limit edged is gently mixed, and obtains the solution that solid concentration is 2% to 5% and (depends on assessed polymerization Thing).

Use polymer coating solution parcel substrate particle:

3. take 6000g maltose alcohol to add in top-jet-type fluidised bed granulator.

4. the Coating Solution that would detract from consumption is sprayed onto maltose alcohol with the average spray rate of about 100 to 110 gram/minute On, prepare the lossy coated bead of 1 to 2 w/w %, make up to table 17A such as and tie to the sprinkling pointed by table 17B The aqueous percentage ratio of target (based on dry loss) during bundle.

The most then these particles it are dried.

Embodiment 14,14A to 14H: according to the operation described in embodiment 14, utilize the polymer of 1.0% rate of body weight gain (to depend on Type in table 17A and table 17B) prepare lossy coated bead.

Table 17A

The e ' and e of test coated bead "

A:DBS: dibutyl sebacate (plasticizer)

B:PG: propylene glycol (plasticizer)

The non-record of NR

1: purchased from Evonik companyRL30D is ethyl acrylate, methyl methacrylate and a small amount of band season The copolymer of the methacrylate of ammonium group

2: purchased from Evonik companyRS30D is ethyl acrylate, methyl methacrylate and a small amount of band season The copolymer of the methacrylate of ammonium group

Table 17B

The e ' and e of test coated bead "

A:DBS: dibutyl sebacate (plasticizer)

B:PG: propylene glycol (plasticizer)

The non-record of NR

3: with trade name KollicoatPurchased from BASF AG

4: with trade name KollicoatPurchased from BASF AG

Embodiment 15: evaluate tablet excipient (including adding corn starch and mesoporous silica) and avoid during sintering Adhering of tablets is to the ability on mould

Add corn starch and mesoporous silica enables tablet to have anti-adhesion properties, moreover it is possible to control sintered ODT Moisture in tablet blend, thus prevent during sintering by radio-frequency (RF) energy adhering of tablets on mould.

Part A: use the acetaminophen preparation tablet of hydroxyethyl cellulose coated bead and encapsulating:

The tablet of weight 600mg is produced by the formula in table 18.Coating maltose alcohol is placed in fluidized bed coating equipment, uses Hydroxyethyl cellulose aqueous solution (embodiment 11B) parcel containing 1% hydroxyethyl cellulose, 1% glycerol and 1% sodium citrate.

Then the formula in use table 18 prepares blend.The acetaminophen of encapsulating, sucralose and Fructus Vitis viniferae are rectified Plastic bag is put in taste agent, and hand mix is until uniformly.Then this mixture is transferred in Turbula blender, form sediment with Semen Maydis Powder, Syloid and coating maltose alcohol mix 5 minutes.

In order to prepare tablet, blend is filled in 12.5mm circular die, sinters about 0.8 second with 27MHz radio frequency, shape Become oral cavity disintegration tablet.Use different amounts of corn starch (in the range of 0.625% to 2.5%) and Syloid (0.25% to In the range of 1.0%), the optimum amount of corn starch and Syloid is determined by experimental design model.By collapsing that USP 24 records The solution time is shorter than 30 seconds, and the friability of tablet is 1.68 less than desired value 3% (taking 3 tablets, fall 15 times respectively).

Table 18

1: with trade name acetaminophenPurchased from Aptalis company

2: purchased from Grain Processing company

3: as mesoporous silica purchased from W.R.Grace company

Specific embodiments of the present invention are shown by following example.The present invention is not limited in these embodiments The concrete restriction illustrated.

It is understood that, although combine the detailed description of the invention of the present invention and described the present invention, but described above be intended to The illustrative not limiting the scope of the present invention limited by following claims.Other aspects, advantage and amendment are all in right In the range of claim.

Claims (22)

1., for the method manufacturing the tablet comprising at least one pharmaceutically active agents, said method comprising the steps of: to Powder blend applying radio-frequency (RF) energy to sinter described tablet into by described powder blend, and wherein said powder blend comprises Lossy coated bead and at least one pharmaceutically active agents described, wherein said lossy coated bead comprises base material, institute Stating base material and be enclosed with the lossy coating containing at least one activator at least in part, wherein said base material has and is more than The Q-value of 100, and described activator has the Q-value less than 75.

Method the most according to claim 1, wherein said activator has the Q-value less than 50.

Method the most according to claim 1, wherein said base material has the Q-value more than 200.

Method the most according to claim 2, wherein said base material has the Q-value more than 200.

Method the most according to claim 1, wherein said lossy coated bead has the Q-value more than 100.

Method the most according to claim 1, wherein said powder blend has the Q-value more than 100.

Method the most according to claim 1, wherein said powder blend comprises the described lossy of at least 20 weight % Coated bead.

Method the most according to claim 1, wherein said lossy coated bead comprises about 0.1 weight % to about 2 weights At least one activator described of amount %.

Method the most according to claim 1, wherein said lossy coated bead comprises about 0.1 weight % to about 3 weights The water of amount %.

Method the most according to claim 1, wherein said tablet is when being placed on tongue, less than in about 30 seconds in mouth Disintegrate.

11. methods according to claim 1, wherein said radio-frequency (RF) energy has the about 13MHz frequency to about 40MHz.

12. methods according to claim 1, wherein said tablet is formed in tablet die.

13. methods according to claim 1, wherein said activator is selected from following polymer: cellulose, water-base cement The copolymer of body, polymethacrylates, polyvinyls, protein, polysaccharide and these materials.

14. methods according to claim 1, wherein said activator is hydroxypropyl cellulose or hydroxyethyl cellulose.

15. methods according to claim 1, wherein said base material comprises starch, sugar alcohol or sugar.

16. methods according to claim 1, wherein said base material comprises maltose alcohol or mannitol.

17. methods according to claim 1, wherein said base material comprises described pharmaceutically active agents.

18. methods according to claim 1, the friability of wherein said tablet is less than about 5%.

19. methods according to claim 1, wherein said tablet also comprises deicer.

20. methods according to claim 1, wherein said tablet also comprises plasticizer.

21. 1 kinds, for the method manufacturing the tablet comprising at least one pharmaceutically active agents, said method comprising the steps of: to Powder blend applying radio-frequency (RF) energy to sinter described tablet into by described powder blend, and wherein said powder blend comprises Lossy coated bead and at least one pharmaceutically active agents described, wherein said lossy coated bead comprises base material, institute Stating base material and be enclosed with the lossy coating containing at least one activator at least in part, the Q-value of wherein said activator is not Half to the Q-value of described base material.

The tablet of 22. 1 kinds of sintering comprising lossy coated bead and at least one pharmaceutically active agents, wherein said Lossy coated bead comprises base material, and it is lossy that described base material is enclosed with containing at least one activator at least in part Coating, wherein said base material has the Q-value more than 100, and described activator has the Q-value less than 75.